Bioavailability of immediate and controlled release
formulations of lithium carbonate
Biodisponibilidade de formulações de liberação imediata e controlada de
carbonato de lítio
Luciana Vismari, Maria Laura N Pires, Ana Amélia Benedito-Silva and Helena Maria Calil
Department of Psychobiology, Federal University of São Paulo (Unifesp/EPM). São Paulo, SP, Brazil
Sponsored by the CNPq (Processes ns. 132203/98-7 and 301596/79-4 – National Research Council Master and Researcher I Grants) and from the Association Fund of Incentive to Psychopharmacology (AFIP). Part of the Master thesis “Study on the Bioavailability and Chronobiology of Lithium in Healthy Volunteers”, presented to the Department of Psychobiology of the Unifesp/EPM, 2000.
This study was partially presented as a poster in the Brazilian Congress of Psychiatry in the city of Fortaleza, state of Ceará, in October 1999. Abstract
Keywords
Resumo
Descritores
Introduction/Objectives: Controlled-release lithium formulations were developed to minimize elevated blood peaks, related to side-effects and intoxications. However, there is little information about the bioavailability of the only controlled-release lithium formulation available in Brazil. The objective of this study was to compare the bioavailability of controlled-release and immediate-release lithium formulations, after single and multiple doses. Methods: Twelve healthy volunteers received 900 mg of immediate-release or controlled-release lithium carbonate in single or multiple doses during 9 days. After single dose administration, the following parameters were analyzed for each formulation: maximum lithium concentration (Cmax); time to reach Cmax (tmax); area under the curve of serum concentration versus time (AUC0-12 and AUC0-∞) and the elimination half-life (t1/2 elim.). After multiple doses, Cmax; tmax; AUC0-12; mean (Cmean) and minimum drug concentration (Cmin) and degree of fluctuation (DF) were analyzed. A 90% confidence interval (90%CI) for the ratio between the AUCs for each formulation was constructed.
Results/Discussion: Following single dose, the two formulations were bioequivalent; however, they were not after multiple doses. This fact could be a consequence of methodological limitations of lithium level’s measurements since, following single dose, these levels could not be detected at time periods 24 and 48h in many volunteers, compromising the calculation of t1/2 elim ,and consequently of the AUC0-∞ and the 90%CI to the ratio of these areas. Therefore, the bioequivalence found after single dose may be an unreliable result.
Lithium carbonate. Bioavailability. Dosage forms. Single dose. Doses repetition. Healthy man.
Introdução/Objetivo: Formulações de liberação controlada de lítio foram produzidas para minimizar picos sangüíneos elevados relacionados a efeitos colaterais e intoxicações. No entanto, o único produto com liberação controlada de lítio disponível no Brasil possui poucas informações a respeito de sua biodisponibilidade. O presente estudo tem como objetivo comparar a biodisponibilidade de formulações de liberação imediata e controlada de carbonato de lítio, após administração de doses única e múltiplas.
Métodos: Voluntários sadios (n=12) receberam 900 mg de carbonato de lítio de liberação imediata ou controlada, em dose única ou durante nove dias. Após dose única, foram analisados, para cada formulação, concentração sangüínea máxima de lítio (Cmáx), tempo para atingir essas concentrações (tmáx), área sob a curva da concentração sangüínea versus tempo (ASC0-12 e ASC0-∞) e tempo de meia-vida de eliminação (t1/2 elim.). Após doses múltiplas, Cmáx, tmáx, ASC0-12, concentração sangüínea média (Cmédio) e mínima (Cmin) de lítio e porcentagem de flutuação dessas concentrações (%F) foram calculadas. Calculou-se um intervalo de confiança de 90% (IC90%) para a razão entre as ASC de cada formulação.
Resultados/Discussão: Após dose única, as duas formulações mostraram-se bioequivalentes; no entanto,
não o foram após doses múltiplas. Esse fato talvez decorra das limitações do método de determinação da litemia, uma vez que, após dose única, as concentrações nos períodos de tempo 24 e 48 horas não foram detectáveis para muitos voluntários, prejudicando o cálculo do t1/2 elim. e, conseqüentemente, o da ASC0-∞ e do IC90% para a razão dessas áreas. Logo, a bioequivalência encontrada após dose única pode não ser um resultado confiável.
Introduction
The prophylactic-therapeutic action of lithium salts in bipo-lar disorder has been confirmed by many studies in several countries.1,3 The carbonate salt has been chosen for pills and
capsules, as it is less hygroscopic and less irritating to the gastric mucosa than others, especially chloride.4 It is
commer-cially available in immediate-release formulations. However, this kind of formulation produces high lithium blood levels, which have been associated to side effects and intoxication originated from the product.5
Alternatively, the modified or controlled-release formula-tions provide specific advantages over immediate-release for-mulations, due to decreased blood peaks secondary to a showed absorption rate. The elimination phase of the drug’s decreasing curve is altered, causing an increase in the elimi-nation half-life, allowing to the administration of a daily single dose instead of the traditional divided doses – two or three (b.i.d. or t.i.d.)–, diminishing the chance of patients forget-ting the drug, and increasing their compliance. Besides, the chance of survival after an overdose rises as there is more time for a gastric lavage before the plasmatic concentration reaches its peak value.6-8
There have been several studies comparing the bioavailability of the controlled-release formulations existent in the world mar-ket.9-11 Nevertheless, there is scarce information about the
bioavailability of the only product with controlled-release lithium available in Brazil.12
The objective of this study is to compare the bioavailability of controlled and immediate-release formulations of lithium car-bonate (Carbolithium CR 450 mg and Carbolithium 300 mg; Eurofarma Laboratórios Ltda, SP, Brazil) after administration of single and multiple (nine days) doses to healthy volunteers.
Materials and Methods
Twelve healthy, Caucasian, male volunteers (aging 18 to 30), selected through an advertisement in the premises of the Fed-eral University of São Paulo (Unifesp) participated in the study. The Institution’s Research Ethics Committee previously ap-proved the study. The volunteers gave written informed con-sent before beginning the study. They all went through physi-cal and psychiatric assessment, with the Structured Cliniphysi-cal Interview for the DSM-IV axis I disorders – non- patient edi-tion13 and routine laboratory tests (hemogram, creatinine, uric
acid, glutamic oxalacetic transaminase [GOT], glutamic piruvic transaminase [GPT], thyroid-stimulating hormone [TSH], free tetraiodothyronine [T4-], cholesterol, triglycerids, urea, glucose and magnesium, sodium, potassium and chlorine). The pres-ence of any result with a clinically significant deviation from the normality was an exclusion criterion.
The volunteers were instructed to abstain from consuming alcohol, drugs and any other kind of medications during the study’s period.
We used immediate-release lithium carbonate (Carbolithium 300 mg – lot 016.98), and controlled-release (Carbolithium CR 450 mg – lot 004.98) formulations, donated by Eurofarma Laboratórios Ltda (SP, Brazil).
The study consisted in a two-phase cross-over study (I: single dose and II: multiple doses) in which the 12 volunteers were randomically divided in two groups (A and B). They were instructed to fast for 10 hours before the beginning of the procedure and 4 hours after drug administration. In phase I, the volunteers received 900 mg of lithium carbonate as a single dose at 8:00h A.M. (group A: immediate release formu-lation and group B controlled-release formuformu-lation). Blood samples 5 ml were collected immediately before the ingestion of the drug (time 0) and after the time intervals 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 hours. A week after, the procedure was repeated, and treatments were alternated.
In phase II, both groups of volunteers (A and B) received 900 mg/day of lithium carbonate during nine days. Group A re-ceived 2 immediate-release pills at 8:00 A.M. and 1 pill at 08:00 P.M., and group B received 1 controlled-release pill at 8:00 A.M and other at 08:00 P.M. Blood samples were collected on the eighth day of treatment, immediately before the morning inges-tion of the drug (time zero) and afterwards in the same time intervals (0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48). The blood lithium was determined in triplicate with the ion-selective electrode tech-nique (EasyLyte Na/K/Cl/Li Analyzer – Medica Corporation, Massachusetts, USA).
Pharmacokinetic parameters were determined according to the rules of the Food and Drug Administration (FDA),14 of the
United States Pharmacopeia15 and of the National Sanitary
Vigi-lance Agency from Brazil.16
• Phase I – single dose: AUC: area under the curve (in mEq.h/l) delineated by the drug’s concentration versus time, calculated by the trapezoidal method from time zero to time 12 h (AUC0-t) and extrapolated to infinitum (AUC 0-∞); t1/2: elimination half-life time, corresponds to the time
needed for a drug to reach half of the initial blood concentration; Cmax: corresponds to the maximum lithium concentration, in mEq./l, directly obtained from individu-al curves of concentration vs. time; Tmax: refers to the time, in hours, in which Cmax was achieved. This value was directly obtained from individual curves of blood concentration vs. time.
• Phase II – multiple doses: AUC0-12; Cmax; Tmax; Cmin: drug concentration at the end of each interval between doses, in the steady state, directly obtained from the graph of blood concentration vs. time for each subject, in mEq/l; Cmean: mean drug concentration (mEq/l) in the steady state, obtained by the equation: Cmean = (AUC0-t)/τ, where τ corresponds to the interval between doses (in this case, 12 hours); %F: the degree of fluctuation of drug concentrations, calculated by the equation: %F = [(Cmáx – Cmin)/ Cmean ] x 100%.
considered bioequivalent when the antilogs of the 90%CIs for the ratios of AUC means fall between 0.8 and 1.25.
The parameters AUC0-t and Cmax were submitted to analysis of variance (ANOVA) to assess if there were effects formulation’s order of administration of the i.e., of phase (I and II) and of treatment (immediate and controlled-release).
The other pharmacokinetic parameters of immediate and con-trolled-release formulations were compared with paired t test, except for the Tmax, for which it has been recommended a non-parametric analysis (Wilcoxon’s test).17
The assessment of adverse effects of the two lithium carbon-ate formulations was performed by a Side Effects Scale, devel-oped by the researchers and composed of the 21 main adverse effects cited in the literature for this drug. For each of them, the volunteer should choose the option that better described its intensity at the moment, which varied from the degree zero (ab-sence of effect) to 3 (great effect). This scale was administered in phase I (before the drug administration and 3, 6 and 12 hours after it) and in phase II (before the beginning of the treatment and after eight days).
Results
The sample was composed by 12 healthy, young (age 23.7±3.4), male volunteers with a mean body mass of 74.7±9.6 Kg, mostly students or employees in the University.
During phase I (single dose administration), lithium blood levels in several collecting time-points were under the assay’s sensitivity level (0.2 mEq/l). Therefore, only in 7 out of 12 collections the concentrations were detectable in all volun-teers: time 0 (before the ingestion of lithium, considered as blood lithium zero) and 2, 3, 4, 6, 8 and 12 hours after the drug administration.
A three-way ANOVA revealed absence of order effects(firstly immediate or controlled release) or treatment (controlled or im-mediate-release formulations) in the measurements of AUC (F=0.11 and 1.48, respectively, p>0.05) and Cmax (F=0.66 and 4.50, respectively; p>0.05), but a significant phase effect (single or multiple doses) in AUC0-t and Cmax (F=91.5 and 36.51; respec-tively, p<0.001). The ANOVA also revealed a significant inter-action between phase and treatment for AUC (F=147.6; p<0.001) and Cmax (F=48.96; p<0.001).
Data analysis from phase I (single dose) showed that the controlled-release formulation produced smaller AUC0-12 and Cmax when compared to the immediate-release formulation (Table 1). However, there was no difference between the for-mulations’ AUC0-∞, since the 90%CI for the mean differences between formulations was into the values pre-established by the FDA (0.8 to 1.25). The statistical analysis of the remaining parameters showed that the controlled-release formulation produced a significantly higher Tmax than the immediate-re-lease formulation (z=2.803, p<0.01), but the t1/2elim. was not dif-ferent for both formulations (t=-1.37; p>0.05).
The values (mean ± standard deviation) of the curve of lithium concentration versus time in healthy volunteers after a 900-mg single dose of immediate and controlled-release lithium carbonate are in Figure 1. The individual curves
pro-Table 1 - Phamacokinetic parameters (mean ± standard deviation) and confidence intervals obtained after administration of an immediate and controlled-release single dose of 900 mg of lithium carbonate in healthy volunteers (n=12).
Pharmacokinetic Immediate-release Controlled-release IC90%* parameters formulation formulation
Cmax (mEq/l) 0.85±0.12 0.59±0.13**
AUC0-12 (mEq.h/l) 5.99±0.83 4.71±0.68 0.73-0.85 AUC0-∞(mEq.h/l) 24.65±7.92 24.71±4.28 0.89-1.24 Tmax (h) 2.42±0.85 4.59±1.61***
t1/2 elim. (h) 34.25±10.75 39±6.71****
*Lower Limit (LL) and Upper Limit (UL) of the 90% confidence interval for the mean difference between both formulations, calculated using data transformed into logarithm;
**Duncan’s test, p < 0.05;
***Wilcoxon’s test (non parametric), p< 0.01; ****paired t test, p> 0.05.
duced by both formulations are in Figure 2. It is noteworthy that volunteers 4, 6, 8, 11 and 12 showed very similar or even equal Tmax values for both formulations. Regarding the Cmax produced by both products, they were similar in volunteers 4 and 11.
The data analysis of Phase II (multiple-dose administration) revealed that both formulations were similar as regards the Cmax (Table 2). However, the time to reach the maximum concentration, or Tmax, was longer after the administration of the controlled-release formulation. Formulations also differed as concerns the AUC0-12, since the confidence interval for mean differences be-tween formulations was not within the limits pre-established by the FDA (0.8 to 1.25). For the remaining parameters, the con-trolled-release formulation produced a higher mean minimum blood concentrations of the drug than the immediate-release for-mulation, with a lower percentage of concentration fluctuation (%F) along the day. The values (mean ± standard deviation) of the curve of blood lithium concentration versus time in healthy volunteers (n=12) after multiple doses of immediate-release (Carbolithium 300 mg) and controlled-release (Carbolithium CR 450 mg) lithium carbonate for 9 days are in Figure 3, whereas the individual curves of these formulations are in Figure 4. It is note-worthy that volunteers 6, 10, 11 and 12 showed similar Tmax val-ues for both formulations. As for lithium blood concentrations in volunteer 12, they did not vary over time after the administration of controlled-release formulation.
Figure 1 - Lithium serum concentrations (mean ± standard deviation) versus time in healthy volunteers (n=12) after 900 mg of immediate (Carbolithium 300 mg) and controlled-release (Carbolithium CR 450 mg)
lithium carbonate in single dose.
0.00 0.20 0.40 0.60 0.80 1.00 1.20
0 2 4 6 8 10 12
Carbolithium 300mg Carbolithium CR 450mg
Lithium concentrations
(mEq/l)
Analysis of the Side-Effects Scale
The reports recorded in the Side-Effects Scale show that eight volunteers had softened stools after a single dose of controlled-release formulation and only two of them after the administration of the immediate-release formulation. The re-port of softened stools was also the most imre-portant effect during the administration of multiple doses, having been re-ported by five volunteers who received the controlled-release formulation and by two volunteers who received the immedi-ate-release formulation. Some volunteers also described sleep alterations (n=6), irritability (n=2) or abdominal pain (n=4), which occurred more frequently with both formulations in the beginning of the treatment (3 or 4 days).
Discussion
The results of the study allow us to state that after a single dose both formulations were bioequivalent regarding the drug amount in the body in the time interval zero extrapolated to
Table 2 - Pharmacokinetic parameters (mean ± standard deviation) and confidence intervals obtained after administration of multiple doses (9 days) of 900 mg/day of immediate and controlled-release lithium carbonate in healthy volunteers (n=12).
Pharmacokinetic Immediate-release controlled-release IC90%* parameters formulation formulation
Cmax (mEq/l) 0.99±0.20 1.05±0.18
AUC0-12 (mEq.h/l) 8.63±1.82 10.44±1.92 1.15-1.28 Tmax (h) 1.83±0.64 3.85±0.41**
Cmean (mEq/l) 0.72±0.15 0.87±0.16*** Cmin (mEq/l) 0.55±0.13 0.73±0.18*** %F (%) 61.16±15.31 40.45±30.42***
*Lower limit (LL) and Upper limit (UP) of the 90% confidence interval for the mean difference between both formulations, calculated using data transformed into Neperian logarithm. **Wilcoxon’s test, p< 0.01.
***paired t test, p< 0.03.
Figure 3 - Lithium serum concentrations (mean ± standard deviation) versus time in healthy volunteers (n=12) who received 900 mg of immediate (Carbolithium 300 mg) and controlled-release (Carbolithium CR 450 mg)
lithium carbonate in multiple doses.
0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40
0 2 4 6 8 10 12
Carbolithium 300mg Carbolithium CR 450mg
Lithium concentrations
(mEq/l)
time(h)
Figure 2 - Lithium serum concentrations versus time in healthy volunteers (n=12) after 900 mg of immediate (∆∆∆∆∆: Carbolithium 300 mg)
and controlled-release ( : Carbolithium CR 450 mg) lithium carbonate
in single dose.
Volunteer 1
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 2
0 0.6 1.2
0 12 24 36 48
Volunteer 3
0 0.6 1.2
0 12 24 36 48
Volunteer 4
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 5
0 0.6 1.2
0 12 24 36 48
Volunteer 6
0 0.6 1.2
0 12 24 36 48
Volunteer 7
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 8
0 0.6 1.2
0 12 24 36 48
Volunteer 9
0 0.6 1.2
0 12 24 36 48
Volunteer 10
0 0.4 0.8 1.2
0 12 24 36 48 time (h)
Volunteer 11
0 0.6 1.2
0 12 24 36 48 time (h)
Volunteer 12
0 12 24 36 48 time (h) 1.2
0.6
0
Lithium concentration (mEq/l)
Lithium concentration (mEq/l)
Lithium concentration (mEq/l)
Lithium concentration (mEq/l)
Figure 4 - Lithium serum concentrations versus time in healthy volunteers (n=12) who received 900 mg/day of immediate (∆∆∆∆∆: Carbolithium 300 mg)
and controlled-release ( : Carbolithium CR 450 mg) lithium carbonate in
multiple doses (9 days).
Volunteer 1
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 2
0 0.6 1.2
0 12 24 36 48
Volunteer 3
0 0.6 1.2
0 12 24 36 48 Volunteer 4
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 5
0 0.6 1.2
0 12 24 36 48
Volunteer 6
0 0.4 0.8 1.2
0 12 24 36 48 Volunteer 7
0 0.4 0.8 1.2
0 12 24 36 48
Volunteer 8
0 0.6 1.2
0 12 24 36 48
Volunteer 9
0 0.6 1.2
0 12 24 36 48 Volunteer 10
0 0.4 0.8 1.2
0 12 24 36 48 time (h)
Volunteer 11
0 0.6 1.2
0 12 24 36 48 time (h)
Volunteer 12
0 0.6 1.2
0 12 24 36 48 time (h)
Lithium concentration
(mEq/l)
Lithium concentration
(mEq/l)
Lithium concentration
(mEq/l)
Lithium concentration
infinitum. After a single dose the Cmax of the controlled-re-lease formulation was significantly lower than that of the im-mediate-release. Tmax of controlled-release formulation was sig-nificantly longer than that of immediate release. These results are in accordance with the profile of a controlled-release drug, i.e., the production of lower blood concentrations in a longer time interval after the drug administration.
The elimination half-life time after the single dose treat-ment with controlled-release lithium carbonate (Carbolithium CR 450 mg) and the immediate-release (Carbolithium 300 mg) formulations did not differ (t1/2elim: controlled-release =39±6.71; immediate-release =34.25±10.75). However, it was expected that the controlled-release formulation would have a higher t1/2elim, allowing to a decreased frequency of the treatment administration.6 A possible explanation for this
result is that during this study phase (single dose), due to the fact that some volunteers’ lithium blood after 24 hours were under the assay’s lower detection limit (0.2 mEq/L), their values have not been measured and, therefore, have been considered as absence of lithium. Thus, the determina-tion of the eliminadetermina-tion rate constant (λz), which is calculated based on the individual curve of the plasma concentration vs. time was compromised as well as the determination of the T1/2elim (T1/2elim =(ln2)/λz).
After multiple doses of immediate and controlled-release lithium carbonate formulations there were no bioequivalence, as the 90%CI for the AUCs0-12 was 1.15 - 1.28. The controlled-release formulation produced minimum (Cmin) and mean (Cmean) serum lithium concentrations significantly higher than those of the immediate-release formulation, and a lower fluctuation of concentrations (%F). Knowing that the fluctuation is a mea-sure of the effectiveness of sustained released formulation,5,10
which has been usually related to a lower incidence of side-effects, the results indicate that the controlled-release formula-tion could be a safe alternative for the patients’ treatment. How-ever, both formulations were similar regarding the maximum concentration produced, the opposite to what was expected for
this kind of product. This may be due to the fact that multiple doses of the controlled-release formulation had produced a high incidence of diarrhea, thus leading to sodium loosening in the feces and a consequent lithium retention, as these ions tend to maintain an equilibrium. This might have raised the blood lev-els of this drug, producing a higher Cmax. However, there was no alteration in the Tmax, and the controlled-release formulation continued to produce Cmax after a longer administration time than the immediate-release formulation.
Although lithium has a linear pharmacokinetics with the doses clinically used, the results of the current study showed differ-ences in the bioequivalence after single and multiple doses of both formulations. Possibly the bioequivalence observed after the single dose stems from the problem occurred with levels of detection of lithium after 24 hours in some volunteers. This may have compromised the correct determination of the T1/2elim (as already mentioned) and consequently the estimates of AUC0-∞, as AUC0-∞= AUCt + Ct/λz.
The parameter usually accepted to measure the absorbed drug amount is the AUC, which is proportional to the drug’s absorbed fraction, provided its elimination process be linear. However, many times this process is not linear or can be modi-fied by the excipient, making the elimination not constant. Therefore, equal AUCs are not a sufficient proof that the ab-sorbed fractions are equal, even in a linear elimination pro-cess.18 Due to that, other parameters have been proposed for
these studies.19-21
Other questionable aspect is whether the pharmacological bioequivalence is a measure of the therapeutic equivalence of both products, i.e., the absence of pharmacological bioequivalence necessarily would indicate a lack of thera-peutic equivalence?22
Acknowledgments
To the National Research Council (CNPq); the Association Fund of Incentive to Psychopharmacology (AFIP) for their fi-nancial sponsoring.
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Correspondence: Helena M. Calil
Rua Botucatu, 862, 1o andar, Vila Clementino
04023-062 São Paulo, SP, Brasil Tel.: (0xx11) 5539-0155
Fax: (0xx11) 5572-5092
E-mail: hmcalil@psicobio.epm.br 12. Storpirtis S, Ferraz HG, Porta V, Consiglieri VO, Ting HC. Relatório
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